1. Field of the Invention
The present invention relates to methods and formulations for improving photodynamic therapy (PDT). In particular the present invention relates to methods to reduce side-effects of PDT.
2. Information Disclosure Statement
Photodynamic therapy (PDT) is a well-accepted procedure for treating a variety of diseases and conditions. Of particular importance is PDT's success in fighting cancer, but it also has beneficial uses in many fields including various hyperproliferative skin conditions such as psoriasis, cosmetic hair removal, ocular disease treatments and wound treatment. PDT's usefulness is evident in its ability to selectively target diseased cells while leaving healthy cells unaffected.
PDT treatments generally consist of three steps. The first step involves systemically or locally introducing photosensitizers or their precursors to a patient. Systemic administration involves injection of the photosensitizer into the bloodstream, whereas local administration may involve the use of a cream or lotion for dermatological application. Photosensitizers, such as porphyrins or chlorins, exhibit the characteristic that they are nonreactive unless exposed to light of certain wavelengths. The next step involves allowing photosensitizers to preferentially accumulate around diseased tissue. Photosensitizers tend to be taken up by abnormally proliferative cells such as cancerous cells. After a sufficient period of time, the body flushes most of the photosensitizers, but proliferative cells retain them for a longer period. The result is that photosensitizers then substantially exist only in close proximity to abnormal cells. Photosensitizers applied locally generally require less time to accumulate with diseased tissue than those applied systemically. Finally, the site is to be treated with light of a suitable wavelength. This serves to activate the photosensitizers and produce cytotoxic effects. Because their destructive range is very small, the destructive effect is limited only to those cells that are close to the photosensitizers. Because only primarily cancerous or abnormally growing cells remain close to photosensitizers, these abnormal cells are destroyed and healthy tissue is spared.
Although PDT is an improvement over other treatments in many applications, and especially in cosmetic applications such as hair removal, it still suffers from some drawbacks. One major side-effect of photodynamic therapy is photosensitization of the skin and eyes after a full PDT treatment (i.e. application of photosensitizers and subsequent irradiation. As shown in FIG. 1, although the photosensitizer concentration in cancerous tissue becomes substantially greater than the concentration in other tissue, a significant concentration of photosensitizer remains in healthy tissue, such as the skin, for a substantial period of time after the photosensitizer is administered. If a patient is exposed to sunlight, indoor light, or any other light source that contains the activation wavelength, widespread and severe erythema can result. In such cases of systemic administration of photosensitizers, the patient's entire skin becomes photosensitized. In those cases where photosensitizers are topically applied, the area of skin that was treated will remain photosensitized. Patients must avoid sunlight and bright indoor light for up to 6 weeks or more to allow the photosensitizer to clear from the skin, and must wear protective clothing and sunglasses should they go outdoors during this period.
Efforts have been made to reduce the intensity and/or duration of skin hypersensitivity after photodynamic therapy. Where possible, the local administration of photosensitizers has been shown to limit skin photosensitivity to only limited areas of the skin. This method, however, is not effective for treatments that require systemic photosensitizer applications or applications over larger body areas. Additionally, local skin photosensitization is only effective if the photosensitive area can be easily shielded from bright light and sunlight. Local administration near the face or hands, for instance, would still pose a threat and be a major inconvenience to the patient.
Efforts have also been made to reduce the concentration of photosensitizer needed for a PDT treatment, so that less time is then required for the photosensitizer to clear from the skin. One way to reduce the needed concentration is to increase the specificity of the photosensitizers used in PDT. Photosensitizers have thus been conjugated with various molecules, such as target-specific antibodies, that are attracted to certain tissue.
Lipids are any of a heterogeneous group of fats and fatlike substances characterised by being water insoluble and being extractable by nonpolar solvents such as alcohol, ether, chloroform, and benzene. Lipids, which are easily stored in the body, serve as a source of fuel, are an important constituent of cell structure and serve other biological functions. Compound lipids comprise the glycolipids, lipoproteins and phospholipids. Phospholipids are the major structural lipids of most cellular membranes, and contain phosphate, usually as a diester.
Phospholipids have been utilized in various ways, such as in the manufacture of liposomes. Liposomes are submicron, hollow vesicles consisting of hydrated, synthetic phospholipids arranged in a bilayer structure. Attempts have been made to prepare formulations wherein non-polar, poorly water-soluble photosensitizers are encased in liposomes. (for example, see U.S. Pat. No. 6,074,666) Non-polar, hydrophobic photosensitizers include porphyrins, some porphyrin derivatives, chlorins (including benzoporphyrin derivative), purpurins, and phthalocyanines. Although these formulations may have use in aiding administration of photosensitizers, they do not substantially contribute to a reduction in PDT side-effects such as skin phototoxicity.
It would be extremely useful to have a composition and/or method that improves the pharmacokinetic properties of photosensitizers, as well as substantially reduces the severity and length of time of post-PDT skin photosensitization. The present invention addresses these needs.